Tetracalcium phosphate-based materials and processes for their preparation

ABSTRACT

The invention provides (i) a process for preparing tetracalcium phosphate particles, the process comprising the steps of (1) sintering or fusing a powder mixture at a temperature of not lower than 1,400° C., the mixture comprising a powder of calcium source and a powder of phosphorus source in a Ca/P molar ratio of 2/1, and about 0.005 to about 5 parts of an aluminum compound, calculated as Al 2  O 3 , per 100 parts of tetracalcium phosphate to be produced in terms of the theoretical amount, and (2) finely dividing the obtained product; (ii) tetracalcium phosphate particles prepared by said process; (iii) apatite-coated tetracalcium phosphate particles; (iv) a process for preparing the apatite-coated tetracalcium phosphate particles; (v) a tetracalcium phosphate-based setting composition; (vi) a composition for forming a hardening material using coated tetracalcium phosphate particles and an acidic aqueous solution; and (vii) the composition as defined in (vi) in which the acidic aqueous solution can satisfy the concentration relationships as represented below: 
     (a) 25%≦citric acid≦50% 
     (b) 30%≦citric acid+phosphoric acid≦70% 
     (c) 10%≦citric acid-phosphoric acid≦50%

This is a division of application Ser. No. 08/360,330 filed Dec. 21,1994 which in turn is a division of 08/074,154, filed Jun. 9, 1993 nowU.S. Pat. No. 5,409,982 which in turn is a division of 07/728,683 filedJul. 12, 1991 (now abandoned).

INDUSTRIAL FIELD OF THE INVENTION

The present invention relates to tetracalcium phosphate particles usefulas osteosynthetic materials, dental materials and the like, and toprocesses for preparing the same.

The present invention also concerns with tetracalcium phosphateparticles coated with a material, such as apatite, having an affinityfor the living body, processes for preparing the same, and compositionsfor producing cured materials or products which contain suchtetracalcium phosphate particles.

The term "fused state" used herein refers to a state in which thestarting particles have been fluidized as a whole by heating. The term"sintered state" used herein denotes a state in which the startingparticles have not been fluidized by heating but have apparentlydisappeared to form a homogeneous phase. The term "porous state" usedherein means a state in which the starting particles have reacted oneanother on heating, but are present substantially as they are withoutcomplete change of original configuration.

The parts and the percentages used herein are all by weight unlessotherwise specified.

PRIOR ART

Tetracalcium phosphate (Ca₄ (PO₄)₂ O) is a phosphoric acid compoundwhich is the main inorganic component of bones, teeth and so on.Tetracalcium phosphate has a high chemical activity and reacts at roomtemperature with an aqueous solution of, e.g. inorganic acid, saturatedor unsaturated organic acid or a homopolymer or a copolymer ofunsaturated organic acid, or a physiological saline or the like toundergo setting. The obtained hardened material or product has anaffinity for the living body and is useful as an osteosyntheticmaterial, a dental material and so on. 10 In preparation of tetracalciumphosphate, CaCO₃, CaO, Ca(OH)₂ or the like has been used as a Ca source,P₂ O₅, H₃ PO₄, NH₄ H₂ PO₄, (NH₄)₂ HPO₄ or the like as a P source, andCaHPO₄, Ca(H₂ PO₄)₂ or the like as a Ca and P sources. Tetracalciumphosphate can be prepared by Various processes depending on the kinds ofthe materials used. Most predominantly employed is a dry process asshown below in which a mixture of CaCO₃ and CaHPO₄ is calcined:

    2CaCO.sub.3 +2CaHPO.sub.4 →Ca.sub.4 (PO.sub.4).sub.2 O+H.sub.2 O+2CO.sub.2

This process requires calcination of a mixture of the starting particlesat a temperature of about 1,300 to about 1,600° C. and rapidly coolingof the obtained product to about 400° C. (at a cooling rate of not lowerthan about 10° C./min), and gives a product of phosphoric acid compoundscontaining a predominant amount of tetracalcium phosphate. When themixture is calcined at not lower than 1,600° C. in this process, theobtained product is composed of a phase mixture of a porous portion anda semi-fused portion, posing the problem that the obtained product(tetracalcium phosphate) has an irregular quality. Furthermore, thetetracalcium phosphate produced by calcination even at about 1,300° toabout 1,600° C. is highly reactive and very unstable, so that theproduct being cooled at a low cooling rate is caused to absorb watervapor in the atmosphere at 1,200° to 400° C., readily producinghydroxyapatite. With these problems, the process necessitates rigidcontrol of calcining temperature, moisture content in the atmospherewithin the calciner during cooling and cooling rate in order to obtain atetracalcium phosphate of stable quality in a higher yield.

However, it is difficult to remove the moisture in the atmosphere withinthe calciner from the viewpoint of practical operation. Forced coolingof the product in the calciner is technically difficult and causesdamage to refractory materials of calciner wall due to rapid cooling.

Given below are proposed processes for preparing a setting compositioncontaining tetracalcium phosphate particles for use as osteosyntheticmaterials, osteosynthetic fillers, dental cement and so on:

(1) a process comprising admixing tetracalcium phosphate particles withan aqueous solution of TCA cycle-type organic acid;

(2) a process comprising admixing tetracalcium phosphate particles withan aqueous solution which is similar in composition to a tissue fluid inthe living body, such as a physiological saline, a phosphate buffer orthe like;

(3) a process comprising admixing tetracalcium phosphate particles withan aqueous solution of polysaccharide;

(4) a process comprising admixing tetracalcium phosphate particles withan aqueous solution of a homopolymer or a copolymer of unsaturatedorganic acid; and

(5) a process comprising conducting a suitable combination of aboveprocesses (1) to (4).

These setting compositions are provided to clinicians in the form of apowder-liquid pack product comprising a combination of powder and liquidmaterials. In treatment, clinicians must knead the powder and liquidmaterials to obtain a paste or a clay-like mixture for use in anydesired form. Moreover, after application to the affected part, thecomposition must be rapidly set or cured and firmly fixed thereto toexhibit a high biological activity. Yet these requirements can not befully met by the setting or curable compositions produced by any of theabove processes (1) to (5). The tetracalcium phosphate, which is themain component of the powder material, has a high chemical activity andis alkaline. It rapidly undergoes setting reaction when mixed with anacidic aqueous solution and thus is difficult to make into a homogeneouscomposition which can retain a suitable softness for a specific periodof time.

In view of these drawbacks, attempts have been made to assure asufficient treating time and enhance the operational efficiency intreatment. For example, an acid concentration in the liquid material hasbeen reduced or the water content of the composition has been increasedto improve the properties of the composition to be set or to control thesetting time. In respect of the powder material, attempts have been madeto inhibit the setting reaction of tetracalcium phosphate to thegreatest extent possible by admixing therewith apatite, tricalciumphosphate, calcium monohydrogenphosphate, citrate, alkali phosphate orthe like. However, these attempts have resulted in considerableimpairment of properties of tetracalcium phosphate-based settingcomposition, and have failed to enhance the properties for settingreaction sufficiently to make up for the impairment. In short, theattempts have provided no complete solution to the problem.

Tetracalcium phosphate particles have been tentatively mixed with aneutral or substantially neutral aqueous solution. The attempt, however,has markedly decreased the setting reaction rate, whereby thetetracalcium phosphate-based composition has become unlikely to exhibitthe required mechanical and physical characteristics and has been madealkaline, causing the hazard of acting as an irritant in the livingbody.

For the foregoing reasons, tetracalcium phosphate, although suitable foruse as medical materials, dental materials or the like, has not beenindustrially provided in the form of a setting or curable tetracalciumphosphate-based composition having satisfactory properties, because ofdifficulties in handling and inability to fully exhibit the desiredproperties.

Means for Solving the Problems

In view of the foregoing state of the art, the present inventorsconducted extensive research and found the following. When the startingmaterials for use in preparation of tetracalcium phosphate as admixedwith a specific amount of an aluminum compound are heated to a sinteredstate or to a fused state, the tetracalcium phosphate thus obtained canmarkedly alleviate or substantially obviate the prior art problemsentailed in preparation of tetracalcium phosphate.

According to the present invention, there are provided:

(i) a process for preparing tetracalcium phosphate particles, theprocess comprising the steps of (1) sintering or fusing a composition ata temperature of not lower than 1,400° C., the composition comprising apowder of calcium source and a powder of phosphorus source in a Ca/Pmolar ratio of 2/1, and about 0.005 to about 5 parts of an aluminumcompound, calculated as Al₂ O₃, per 100 parts of tetracalcium phosphateto be produced in terms of the theoretical amount, and (2) finelydividing the obtained product; and

(ii) tetracalcium phosphate particles prepared by the process as definedabove in (i).

What are stated in (i) and (ii) will be hereinafter referred to as"first invention".

The present inventors' further research found the following. When thesurface of tetracalcium phosphate particles is coated with apatite, thecoated particles have the combined properties of the two materials, andcan markedly mitigate or substantially overcome the prior art problems.In addition, a setting composition prepared from the obtainedtetracalcium phosphate particles coated with apatite is equivalent orsuperior in properties to conventional setting compositions.

According to the invention, there are further provided:

(i) tetracalcium phosphate particles coated with apatite;

(ii) a process for preparing tetracalcium phosphate particles coatedwith apatite, the process comprising subjecting tetracalcium phosphateparticles to hydration reaction; and

(iii) a tetracalcium phosphate-based setting composition comprising 100parts by weight of the tetracalcium phosphate particles as defined abovein (i) and about 5 to about 80 parts by weight of an aqueous solution ofan acid, calculated as an acid.

What are stated above in (i), (ii) and (iii) will be hereinafterreferred to as "second invention".

The present inventors' additional research revealed the following. Anacidic aqueous solution predominantly containing citric acid andphosphoric acid is kneaded with a powder mixture predominantlycontaining tetracalcium phosphate particles having a double structure(the term "double structure" used herein refers to a structure whereinthe tetracalcium phosphate particles are coated with apatite or likesubstance which is harmless to the living body or which has an affinityfor the living body). The mixture can pronouncedly moderate orsubstantially solve the prior art problems.

In other words, according to the invention, there are also provided:

(i) a composition for forming a hardening material of high strength, thecomposition comprising 100 parts by weight of a powder mixturepredominantly containing tetracalcium phosphate particles coated with asubstance which is harmless to the living body and which has an affinityfor the living body, and about 5 to about 80 parts by weight, calculatedas an acid, of an acidic aqueous solution predominantly containingcitric acid and phosphoric acid; and

(ii) a composition for forming a hardening material of high strength asdefined above in (i) in which the acidic aqueous solution is able tosatisfy all the concentration relations given below

(a) 25%≦citric acid≦50%

(b) 30%≦citric acid+phosphoric acid≦70%

(c) 10%≦citric acid-phosphoric acid≦50%.

What are stated above in (i) and (ii) will be hereinafter referred to as"third invention".

The first, second and third inventions will be described below ingreater detail.

I. First Invention

The starting materials for preparation of tetracalcium phosphateaccording to the first invention may be the same as those used in theabove-mentioned conventional processes. Yet when the obtainedtetracalcium phosphate is used as a biological material, it is desirableto use acceptable food additives such as CaHPO₄, CaHPO₄.2H₂ O, CaCO₃,Ca₃ (PO₄)₂ and so on from the viewpoint of safety and the like. Theseadditives are used in the form of particles usually having a particlesize of up to 20 μm and an average particle size of about 5 μm.

Examples of aluminum compounds for use in preparation of tetracalciumphosphate are Al₂ O₃, Al(OH)₃, Al(PO)₃, ALPO₄, Al(H₂ PO₄)₃, AlB₂, AlCl₃,AlF₃, AlI₃, Al₂ (SiO₃)₃, Al₂ (SO₄)₃, Al₂ TiO₅, etc. These compounds areusable singly or at least two of them can be used in mixture. Among theabove examples, Al₂ O₃ is desirable in view of the homogeneity ofcalcination product, control of calcining temperature and color ofreaction product. The aluminum compound is used in the form of particlesusually up to 20 μm in particle size and about 5 μm in average particlesize. Alternatively Al₂ O₃ may be partially replaced with a compoundsuch as boron oxide (B₂ O₃) in the IIIb group (to which A1 pertains) inthe short form of the periodic table.

The composition for use in the first invention comprises the Ca and Psource materials in a Ca/P molar ratio of 2/1, and the aluminum compoundin an amount of about 0.005 to about 5 parts in terms of Al₂ O₃ per 100parts of tetracalcium phosphate to be produced in terms of thetheoretical amount. The mixture is calcined at not lower than 1,400° C.to a sintered or fused state, and left to stand for cooling in acalciner. The cooling rate may widely vary depending on the amount ofstarting materials used, the volume and structure of the calciner, andso on. In any case, the calcination product is cooled in the firstinvention at a lower rate than the rapid cooling conventionally done ata rate of not lower than 10° C./min. If before calcination, the mixturemay be molded to an extent of not being collapsible, it eliminates theuse of a container for the powder mixture, facilitates the handling,enables effective use of the volume of calciner interior, and hence isadvantageous. A preferred amount of the aluminum compound is about 1 toabout 2 parts per 100 parts of tetracalcium phosphate to be produced interms of the theoretical amount. A preferred calcining temperatureranges from about 1,500° to about 1,550° C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a relationship between the amount of Al₂ O₃ (per 100 partsof tetracalcium phosphate to be produced, calculated as the theoreticalamount) relative to the amount of Ca and P source powders in a Ca/Pmolar ratio of 2/1, the calcining temperature and the sintered state orthe fused state. FIG. 1 shows that the sintered state and the fusedstate can be widely varied according to the amount of Al₂ O₃ used. Forexample, if the amount of Al₂ O₃ used is 5%, a product in a sinteredstate can be obtained by calcining at about 1,450° C.

FIG. 2 graphically shows a relationship between the amount of Al₂ O₃(per 100 parts of tetracalcium phosphate to be produced calculated asthe theoretical amount) relative to the amount of Ca and P sourcepowders in a Ca/P molar ratio of 2/1, the calcining temperature and theproportion of the tetracalcium phosphate in the reaction product. FIG. 2indicates that the amount of Al₂ O₃ exceeding 5% results in formation ofapatite in excess amount, and therefore should be less than 5%.

FIG. 3 shows x-ray diffraction scans of the products of Example 1 and ofComparative Example 1;

FIG. 4 is an x-ray diffraction scan of the product of Example 2;

FIG. 5 is an x-ray diffraction scan of the product of Example 3;

FIG. 6 is an x-ray diffraction scan of the product of Reference Example2;

FIG. 7 is an x-ray diffraction scan of the product of Example 6;

FIG. 8 is an x-ray diffraction scan of the product of Example 7;

FIG. 9 is a graph showing the relationship in quantity between citricacid and phosphoric acid in the liquid material for setting compositionsof the invention.

The tetracalcium phosphate obtained above is a product made hard by thecalcining process, and contains little or no hydroxyapatite produced.The tetracalcium phosphate powders prepared by conventional calciningprocesses are usually ash-pale white and may be colored partially orwholly thickly dark or ash green due to the influence by a particularkind of materials used, small amounts of impurities, etc., whereby inmost cases the value as a biological product is reduced from anaesthetic viewpoint. In contrast, the Al₂ O₃ -containing tetracalciumphosphate produced by the process of the first invention is uniformlypale blue or turquoise as a whole, namely aesthetically desirable freeof the influence by a particular kind of materials used, small amountsof impurities, etc.

The properties of the tetracalcium phosphate prepared according to thefirst invention can be improved by addition of other additives. Forexample, tetracalcium phosphate is imparted radio-opacity or anti-fungusproperty by addition of at least one compound selected from alkalineearth metal compounds such as BaSO₄, BaCO₃, SrSO₄, SrCO₃, etc. andfluorine-containing compounds such as BaSiF₆, SnF₂, CaF₂, NaF, A1F₃, Na₂SiF₆, etc. These additives may be optionally employed to replace up to60% of the aluminum compound calculated as Al₂ O₃. These additives areused also in the form of particles usually up to 20 μm in particle sizeand about 5 μm in average particle size.

The hardening material of tetracalcium phosphate can be produced fromthe tetracalcium phosphate obtained in the first invention. Suchhardening material can be prepared by mixing (A) a mixture of 100 partsof tetracalcium phosphate particles prepared by the process of the firstinvention and about 0.005 to about 50 parts of a silica-alumina basedamorphous glass powder, and (B) about 30 to about 60%, based on theweight of the mixture, of a TCA cycle-type carboxylic acid or apolyacrylic acid represented by the formula (a) ##STR1## wherein n is1,000 to 100,000.

The tetracalcium phosphate particles for use in production of thehardening material are usually up to 20 μm in particle size and about 5μm in average particle size.

Useful silica-alumina based glass powders include those prepared bymelting and rapidly cooling a powder mixture comprising predominantlysilica and alumina, and optionally, small amounts of calcium, fluorine,sodium, phosphorus, titanium, strontium and the like to obtain avitreous product and pulverizing the product. When the amount of thesilica-alumina based amorphous glass powder is less than 0.005 part per100 parts of tetracalcium phosphate powder, the composition scarcelyexhibits the effect expected to be produced by the addition thereof. Onthe other hand, if more than 50 parts of the glass powder is used, thecured product of the composition tends to show a scarcely improved or adecreased strength. It is preferred to use about 8 to about 15 parts ofsilica-alumina based amorphous glass powder per 100 parts oftetracalcium phosphate powder. The silica-alumina based amorphous glasspowder usually has a particle size of up to 10 μm and about 3 μm on theaverage.

TCA cycle-type carboxylic acids for use in preparation of a hardeningmaterial include citric acid, malonic acid, malic acid, maleic acid,lactic acid, fumaric acid, ascorbic acid, succinic acid, gluconic acid,glutaric acid, pyruvic acid, etc. At least one of these acids and saidpolyacrylic acid is used in the form of an aqueous solution if sorequired. The amount of the TCA cycle-type carboxylic acid and/orpolyacrylic acid is about 30 to about 60% of the combined weight of thetetracalcium phosphate powder and the silica-alumina based amorphousglass powder.

The thus obtained hardening material of tetracalcium phosphate has agreater bulk density in view of the great bulk density of tetracalciumphosphate powder than conventional hardening materials, hence a highcompressive resistance. Therefore the hardening materials thus producedare useful as osteosynthetic materials, dental materials and likebiological materials.

II. Second Invention

The tetracalcium phosphate for use in the second invention is notspecifically limited, e.g. to those prepared by specific processes. Apreferred tetracalcium phosphate is one which contains apatite, calciumoxide or the like in the smallest amount possible. Such high-puritytetracalcium phosphate can be prepared as by a solid phase reactionmethod as represented below in which a CaCO₃ powder is admixed with aCaHPO₄.2H₂ O powder and the mixture is calcined.

    2CaCO.sub.3 +2CaHPO.sub.4.2H.sub.2 O →Ca.sub.4 (PO.sub.4).sub.2 O+2CO.sub.2 +5H.sub.2 O

For preparation of tetracalcium phosphate particles coated with apatiteaccording to the invention, tetracalcium phosphate is pulverized to adesired particle size. The particle size of the powder is notspecifically limited but desirably about 20 μm or less and about 5 μm onthe average, for use as the powder for a setting composition.

Next, the tetracalcium phosphate powder is subjected to hydrationreaction. The hydration reaction proceeds merely by contact of thetetracalcium phosphate powder with water. Yet, to accelerate thereaction, the powder may be heated to a temperature of about 80° toabout 100° C., preferably to about 95° C., or a reaction accelerator maybe added. Useful reaction accelerators include organic acids such ascitric acid, lactic acid, tartaric acid, succinic acid, etc.; saltsthereof; inorganic acids such as hydrochloric acid, phosphoric acid,sulfuric acid, etc.; salts thereof; phosphate buffer solution and likepH adjusting agents for adjustment to neutrality or weak alkalinity;etc. These reaction accelerators are used in the form of an aqueoussolution having a concentration of 1%. or less. In the hydrationreaction, apatite coating is formed on the surface of tetracalciumphosphate particles by the reaction as illustrated below:

    3Ca.sub.4 (PO.sub.4).sub.2 O+3H.sub.2 O→Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2 +2Ca(OH).sub.2

Since apatite is highly stable in an alkaline aqueous solution, thewater to be used in the reaction is preferably alkaline insofar asapatite coating can be formed. When the water to be used has a pH of 8or less, octacalcium phosphate as well as apatite can be produced.Because octacalcium phosphate is a precursor of apatite, the coating isnot necessarily formed of a high-purity apatite. For example, even ifthe coating is formed of a mixture of apatite and octacalcium phosphateor of a high-purity octacalcium phosphate, no practical problem wouldoccur. In the above reaction, the calcium hydroxide is dissolved out inthe water at the same time as the production of apatite, so that thiseliminates the need to add a basic substance. Apatite coating can besatisfactorily produced even in an aqueous solution adjusted toalkalinity. On formation of apatite coating, the reaction rate israpidly decreased, and the surface of particles would not be activatedwithout addition of water or an aqueous solution of an acid. Thereforethe quality of tetracalcium phosphate particles is not impaired due tothe excessive progress of reaction.

The hydration reaction can be effectively conducted by other methods aslisted below:

(a) by contact of tetracalcium phosphate with steam;

(b) by reaction at high temperatures utilizing the moisture in theatmosphere;

(c) by conducting a combination of the methods (a) and (b).

In the method (a), the treating time is substantially the same as in thetreatment with water when the steam has a temperature of 100° C. orless. At a temperature of 100° C. or higher, the treating time isshortened as the temperature rises. For example, when steam of 300° C.is blended in air with tetracalcium phosphate powder, the treating timeis 1 to 120 seconds, preferably about 30 to about 60 seconds.

The method (b) is carried out utilizing the characteristic oftetracalcium phosphate which can be converted into apatite by itspositive absorption of moisture in the atmosphere at a temperature ofabout 300° to about 1,200° C. For, example, when air superheated to 500°C. is blended with tetracalcium phosphate powder, the treating time isabout 1 to about 120 seconds, preferably about 30 to about 60 seconds.

In the method (c), the surface treatment is effected while controllingthe partial pressure of steam and the temperature in the atmosphere. Inother words, the method (c) is a combination of methods (a) and (b). Forexample, when air of 350° C. adjusted to a partial pressure of steam to15 Torr is blended with tetracalcium phosphate powder, the treating timeis about 1 to about 120 seconds, preferably about 30 to about 60seconds.

A tetracalcium phosphate powder having a double structure can beeffectively produced by the following methods without resort tohydration reaction.

a) a method in which ultrafine apatite is adsorbed and fixed on thesurface of tetracalcium phosphate particles; and

b) a method in which apatite in a liquid form is adhered to (ordeposited on) and fixed on the surface of the tetracalcium phosphateparticles.

These methods have the advantage that coating materials are not limitedto apatite. Usable, in other words, is any material which can begradually dissolved in an acidic aqueous solution. For use as abiological material, it is desirable to use materials which are harmlessto the living body (such as tricalcium phosphate, dicalcium phosphatedihydrate, etc.).

The tetracalcium phosphate-based setting composition according to thesecond invention can be- prepared by admixing the tetracalcium phosphateparticles coated with apatite in the above manner with an aqueoussolution of organic acid in an amount of about 5 to about 80%,calculated as an acid, based on the weight of the tetracalcium phosphateparticles. The tetracalcium phosphate particles coated with apatitepreferably have a particle size of about 20 μm or less and about 5 μm onthe average.

Examples of useful organic acids are:

(a) citric acid, tartaric acid, malonic acid, malic acid, maleic acid,lactic acid, succinic acid, fumaric acid, ascorbic acid, gluconic acid,glutaric acid, pyruvic acid and like TCA cycle-type carboxylic acids;

(b) phosphoric acid;

(c) homopolymers of acrylic acid represented by the formula ##STR2##wherein n is 50 to 50,000; (d) copolymers of acrylic acid and itaconicacid represented by the formula ##STR3## wherein 1 is 5 to 10, m is 1 to5 and n is 50 to 50,000; (e) copolymers of acrylic acid and fumaric acidrepresented by the formula ##STR4## wherein 1 is 5 to 10, m is 1 to 5,and n is 50 to 50,000.

These acids are usable singly or at least two of them can be used inmixture. The acid is usually used in the form of an aqueous solutionhaving the materials dissolved in pure water used as a solvent in aconcentration of about 30 to about 70%.

The tetracalcium phosphate-based setting composition thus obtained canfully exhibit any of the inherent properties of tetracalcium phosphatenot at an impaired level but an improved level unlike conventionalsetting compositions. Therefore these setting compositions areparticularly useful as medical materials, dental materials and likebiological materials. III. Third Invention

The hardening material prepared by mixing the powder material and liquidmaterial according to the third invention is equivalent or superior inproperties to conventional biological materials, and also comparable orsuperior in physical and mechanical properties to hardening materials ofknown compositions having no affinity for the living body (such as zincphosphate cement).

We discuss below in more detail the powder material and liquid materialconstituting the setting composition of the third invention and theprocess for preparing a hardening material.

A. Powder Material

The powder material for use in the third invention is tetracalciumphosphates particles coated with a material which is harmless to theliving body and which has an affinity therefor.

A tetracalcium phosphate powder to be used can be prepared by anysuitable process and is desirably a high-purity product (more preferably98% or higher purity) having the lowest possible contents of apatite,calcium oxide and the like. Such high-purity tetracalcium phosphate canbe prepared by a solid phase reaction method as illustrated below, as inthe second invention, in which a mixture of CaCO₃ powder and CaHPO₄.2H₂O powder is calcined:

    2CaCO.sub.3 +2CaHPO.sub.4.2H.sub.2 O Ca.sub.4 (PO.sub.4).sub.2 O+2CO.sub.2 +5H.sub.2 O

In the solid phase reaction method, a tetracalcium phosphate of higherquality can be obtained by adding an alumina powder (Al₂ O₃) totetracalcium phosphate, and heating the mixture to a sintered state(Japanese Unexamined Patent Publication No.180705/1990).

A tetracalcium phosphate powder having a double structure which is usedin the third invention can be produced as follows. First a tetracalciumphosphate is pulverized to a desired particle size and classified. Theparticle size of tetracalcium phosphate particles for use herein may bevaried according to a particular utility of the setting composition andis not specifically limited. It is preferred to adjust tetracalciumphosphate particles to a particle size of about 20 μm or less and about5 μm on the average.

Subsequently a coating material lower in chemical activity thantetracalcium phosphate is applied to the surface of the above-obtainedtetracalcium phosphate particles to form a coating thereon. The coatingmaterial is not specifically limited provided that it is stable instorage and is able to gradually dissolve or to release from the surfaceof tetracalcium phosphate particles on contact with the liquid materialto be described below. The coating material for use in preparing medicalmaterials, dental materials, etc. is required to be harmless to theliving body or to have an affinity therefor. The surface of tetracalciumphosphate particles can be coated by methods not specifically limited.When apatite coating having an affinity for the living body is formed, aliquid-solid phase hydration reaction as represented below is carriedout to obtain tetracalcium phosphate particles having a doublestructure:

    Ca.sub.4 (PO.sub.4).sub.2 O+3H.sub.2 O→Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2 +2Ca(OH).sub.2

Apatite or hydroxyapatite which can be used in the invention includethose having a chemical composition represented by the formula

    Ca.sub.10-z (HPO.sub.4).sub.z (PO.sub.4).sub.6-z (OH).sub.2-z ·nH.sub.2 O

wherein n=0 to 2.5 and z=0 to 1.

Also useful are apatites other than hydroxyapatite such asfluorine-containing apatite having OH group substituted by fluorine,carboxyapatite having OH group substituted by carbonate, etc. which canproduce the same level of effect. The term "apatite" used herein includethese apatites.

The thickness of the apatite coating is not specifically limited,usually in the range of about 0.01 to about 1 μm.

B. Liquid Material

The liquid material for use in the third invention is an aqueoussolution comprising citric acid and phosphoric acid which can satisfyall of the concentration relationships represented by.:

(a) 25%≦citric acid≦50%

(b) 30%≦citric acid+phosphoric acid≦70%

(c) 10%≦citric acid-phosphoric acid≦50%

If citric acid or phosphoric acid is singly used, the desired result isnot obtained, of course, in the invention. Even if these two acids areused, the desired setting compositions can not be obtained unless theconcentration relationships as shown above in (a) to (c) are completelyfulfilled. In the case of not fulfilling them, the obtained compositionscan not give a hardening product having improved properties, or quicklyset or are brought into sand-like or semi-dried clay-like state.

Given below are preferred concentration relationships of citric acid andphosphoric acid in the aqueous solution as the liquid material:

(d) 35%≦citric acid≦45%

(e) 35%≦citric acid+phosphoric acid≦60%

(f) 20%≦citric acid-phosphoric acid≦45%

The most preferred concentration relationships of citric acid andphosphoric acid in the aqueous solution are as follows:

(g) 37%≦citric acid≦42%

(h) 45%≦citric acid+phosphoric acid≦55%

(i) 23%≦citric acid-phosphoric acid≦42%

(j) 7%≦phosphoric acid≦15%

Insofar as citric acid and phosphoric acid in the aqueous solution cansatisfy all of the concentration relationships (a) to (c), the solutionmay incorporate therein up to 10% of at least one of other organic acidsor inorganic acids. Useful organic and inorganic acids are hydrochloricacid, nitric acid, ascorbic acid, polycarboxylic acid, etc.

Optionally malic acid and/or lactic acid can partially replace citricacid (up to 40%) although the use thereof slightly deteriorates theproperties of cured product such as compressive strength, solubility inwater, etc.

The phosphoric acid to be incorporated in the acidic aqueous solution isat least one acid selected from the group consisting of orthophosphoricacid, pyrophosphoric acid, polyphosphoric acid, metaphosphoric acid andphosphorus acid.

C. Process for Forming A Hardening Material

The setting composition according to the third invention can be preparedby admixing about 5 to about 80 parts, calculated as an acid, of theliquid material with 100 parts of the powder material immediately beforeuse. The obtained setting composition is applied in the conventionalmanner to the affected part to be treated, as it is or, when required,as admixed with barium phosphate, calcium fluoride, X-ray contrastmedium, other anti-fungus, medical materials, etc.

In this case, phosphoric acid is reacted with tetracalcium phosphate inthe presence of citric acid, producing apatite and contributing tomarked increase of strength. In conventional setting compositions,phosphoric acid is present as a substance which is detrimental to theliving body, and has been considered a minor component of biologicalcompositions from biological, physical and mechanical viewpoints. Incontrast, phosphoric acid exhibits a unique action in the thirdinvention.

According to the first invention, the following remarkable results canbe obtained.

(1) Sintering or fusing of starting particles eliminates the needs forthe rapid cooling and the dehumidification and drying in calciners asconventionally done.

Therefore tetracalcium phosphate can be obtained using a common calcinerwithout use of a calciner of special structure, consequently at lowercosts.

(2) Tetracalcium phosphate is prepared in a high yield with a highpurity.

(3) A Ca source and a P source powders are not fused by calcination atlower than 1,600° C. although depending on the purity of compounds used.On the other hand, use of Al₂ O₃ according to the first inventionenables sintering and fusing at pronouncedly reduced temperatures. Hencethe first invention is advantageous in terms of energy.

(4) The incorporation of A1₂ O₃ enables calcination at a temperature ina wider range, so that the calcination can notably reduces thevariability of products from lot to lot and the irregularity ofcomposition in products, whereby products of stably uniform quality canbe obtained.

(5) While calcination of only a Ca source and P source compounds givesaesthetically inferior products, calcination thereof in the firstinvention can provide products of uniformly pale blue to turquoise coloror aesthetically excellent properties because of incorporation of Al₂O₃.

(6) Hardening materials obtained using tetracalcium phosphate accordingto the first invention have a great bulk density and a high shatterresistance.

According to the second invention, the following remarkable results canbe produced.

(1) Apatite coating can be formed on the surface of tetracalciumphosphate particles by means of simple procedure without need forspecial apparatus.

(2) The tetracalcium phosphate particles coated with apatite remainstable in quality for an extended period and excellent in resistance toweathering and in storage properties.

(3) The apatite-coated tetracalcium phosphate particles have improvedmechanical and physical properties while retaining the properties oftetracalcium phosphate as biological materials.

(4) Setting compositions having various setting properties can beobtained by adjusting the conditions for surface treatment and thus canbe used for an extended range of applications of tetracalcium phosphateas biological materials.

According to the third invention, the following remarkable results canbe achieved.

(1) The finally obtained cured or hardened product is given pronouncedlyenhanced mechanical and physical properties (compressive strength,curing time, film thickness, etc.) without being impaired in theexcellent properties of tetracalcium phosphate as biological materials.

(2) The obtained setting composition gives hardened products equivalentor superior in mechanical and physical properties to those formed fromconventional biologically inactive setting compositions (such as zincphosphate cement).

(3) The obtained setting composition provides a hardening material ofhigh strength, and thus are usable for a wider range of applications asbiological materials.

(4) Phosphoric acid which has found a narrow range of utility asbiological materials in conventional materials specifically improves theproperties of setting compositions due to the synergistic effectproduced by conjoint use with citric acid.

(5) The obtained setting composition is set after a suitable period(neither too long nor too short), thereby facilitating the operation.

(6) The hardened product has a suitable hardness which leads toenhancement of operational efficiency.

Examples

Given below are Examples and Comparison Examples to clarify the featuresof the invention in further detail.

Example 1

Powdery CaCO₃ and CaHPO₄ having an average particle size of about 5 μmwere mixed together in a molar ratio of 1: 1. Al₂ O₃ was added in anamount of 0.1% based on the weight of the mixture. The resulting mixturewas calcined in a furnace in the atmosphere at 1600° C. for 2 hours forsintering. The sintered body was allowed to stand for cooling in thefurnace and withdrawn therefrom when the sintered body was cooled to400° C.

FIG. 3 shows, in the upper position, the results of X-ray diffractometryusing the sintered body obtained.

The results shown in FIG. 3 reveal that the product substantiallyconsists of tetracalcium phosphate alone.

Comparison Example 1

The same procedure as in Example 1 was repeated except that the mixturewas calcined at 1500° C. The product obtained was porous.

The product was subjected to X-ray diffractometry with the results shownin the lower position in FIG. 3.

The results indicated in FIG. 3 clearly show that the product contains alarge quantity of hydroxyapatite in addition to tetracalcium phosphate.

Example 2

The same procedure as in Example 1 was repeated except that the amountof A1₂ O₃ was adjusted to the range of 0.005 to 50% and that the mixturewas calcined at 1350° to 1600° C.

The product was subjected to X-ray diffractometry with the results shownby the symbols A to F in FIG. 4.

The relationship between the results A to F in FIG. 4 on one hand andthe amount of Al₂ O₃ added and the calcining temperature on the otherhand is as follows.

I. FIG. 4-A

Al₂ O₃ : 50%

Calcining temperature: 1350° C.

II. FIG. 4-B

Al₂ O₃ : 20%

Calcining temperature: 1400° C.

III. FIG. 4-C

Al₂ O3: 10%

Calcining temperature: 1450° C.

IV. FIG. 4-D

Al₂ O₃ : 5%

Calcining temperature: 1450° C.

V. FIG. 4-E

Al₂ O_(3:) 1.5%

Calcining temperature: 1500° C.

VI. FIG. 4-F

Al₂ O₃ : 0.005%

Calcining temperature: 1600° C.

The results A to F shown in FIG. 4 reveal that if the amount of Al₂ O₃is 5% or lower, the melting temperature markedly decreases, wherebytetracalcium phosphate can be satisfactorily produced. However, evenwhen A1₂ O₃ is added in an amount of more than 5%, the meltingtemperature does not markedly decrease and the production oftetracalcium phosphate is inhibited. For this reason, the upper limit ofAl₂ O₃ amount to be added is 5%.

Reference Example 1

To 100 parts of powdery tetracalcium phosphate (average particle size: 5μm) obtained in Example 2 (the amount of A1₂ O₃ added: 1.5%) was added10, 30 or 50 parts of silica-alumina based powdery glass (silica: 50%,alumina: 30% and the total amounts of minor components such as Sr, Ti,Ca and the like: 20%). To 100 parts of the resulting powdery mixture wasadded 50 parts (calculated as an acid) of an aqueous solution containing45% of citric acid, 45% of malic acid or 30% of malic acid and 15% ofpolyacrylic acid (n=about 16000 in the foregoing formula (a)), giving ahardened product.

For comparison, a hardened product was obtained in the same manner asabove with the exception of using a conventional powdery tetracalciumphosphate which does not contain Al₂ O₃.

Twenty four hours after the formation of cured product, each product wastested for compressive resistance (kgf/cm²) with the results shown belowin Table 1.

In Table 1, each symbol indicates the following.

A: silica-alumina based powdery glass was used in an amount of 10 parts

B: silica-alumina based powdery glass was used in an amount of 30 parts

C: silica-alumina based powdery glass was used in an amount of 50 parts

D: citric acid

E: malic acid

F: malic acid+polyacrylic acid

                  TABLE 1                                                         ______________________________________                                                  Acid                                                                          D         E       F                                                 ______________________________________                                        Conventional                                                                  products                                                                      A           653         810     803                                           B           621         773     781                                           C           580         751     766                                           Reference                                                                     Example                                                                       A           1035        1260    1124                                          B           833         978     1031                                          C           720         880     893                                           ______________________________________                                    

The compressive resistance of the hardened product obtained with use oftetracalcium phosphate according to the present invention is about 1.5times that of the hardened product obtained in the same manner using theconventional tetracalcium phosphate.

Example 3

Powdery CaO and P₂ O₅ having a particle size of about 5 μm were mixedtogether in a molar ratio of 4: 1, Further, powdery A1₂ O₃ was addedthereto in an amount of 0.5% based on the theoretical amount of thetetracalcium phosphate to be produced. The resulting mixture wascalcined in a furnace in the atmosphere at 1550° C. for 2 hours forsintering. The sintered body was allowed to stand for cooling in thefurnace. When the sintered body was cooled to 400° C., it was withdrawnfrom the furnace.

The sintered body was subjected to X-ray diffractometry with the resultsshown in the upper position in FIG. 5.

Example 4

Powdery Ca(OH)₂ and Ca(H₂ PO₄)₂ having a particle size of about 5 μmwere mixed together in a molar ratio of 3:1. Powdery Al₂ O₃ was addedthereto in an amount of 1% based on the theoretical amount oftetracalcium phosphate to be produced. The resulting mixture wascalcined in a furnace in the atmosphere at 1500° C. for 2 hours forsintering. The sintered body was allowed to stand for cooling in thefurnace. When the sintered body was cooled to 400° C., it was withdrawnfrom the furnace.

The product obtained was subjected to X-ray diffractometry with theresults shown in the intermediate position in FIG. 5.

Example 5

Powdery CaO and (NH₄)H₂ PO₄ having a particle size of about 5 μm weremixed together in a molar ratio of 2:1. Powdery A1₂ O₃ was added in anamount of 2% based on the theoretical amount of tetracalcium phosphateto be produced. The resulting mixture was calcined in a furnace in theatmosphere at 1500° C. for 2 hours for sintering. The sintered body wasallowed to stand for cooling in the furnace and withdrawn when thesintered body was cooled to 400° C.

The product obtained was subjected to X-ray diffractometry with theresults shown in the lower position in FIG. 5.

Reference Example 2

Powdery CaCO₃ and CaHPO₄.2H₂ O having an average particle size of about5 μm were mixed together in a Ca/P molar ratio of 2:1. The mixture wasshaped and calcined in the atmosphere at 1600° C. for 3 hours to obtaina sintered body. The sintered body was pulverized into particles havingthe maximum particle size of up to 20 μm and an average particle size ofabout 5 μm, giving powdery tetracalcium phosphate.

The product obtained was subjected to X-ray diffractometry with theresults shown in FIG. 6. The results of Table 6 show that the productobtained is a high-purity one substantially consisting of tetracalciumphosphate alone.

In the following examples, the high-purity tetracalcium phosphate thusobtained was used.

Example 6

A 20 g quantity of purified water heated to 95° C. was added to 10 g ofpowdery tetracalcium phosphate. The resulting mixture was separated intoseven portions to provide seven hermetically sealed samples. The sampleswere cured in a constant-temperature bath maintained at 95° C. andwithdrawn therefrom 1 hour, 3 hours, 24 hours, 7 days, 14 days, 30 daysand 60 days after the initiation of the curing, respectively. Eachsample was dried at 105° C. and the particles obtained were subjected toX-ray diffractometry. The results are shown with symbols A to G in FIG.7.

The results A to G in FIG. 7 indicate that the tetracalcium phosphatewas gradually transformed into hydroxyapatite and that the tetracalciumphosphate remained present even in hot water relatively stably for aprolonged period of time.

Example 7

A 2 g quantity of powdery tetracalcium phosphate was dispersed in 1 l ofpurified water and heated at 37° C. and 95° C. for 5 hours,respectively. The powder was separated by filtration and was dried bystanding for 24 hours. The obtained particles were subjected to X-raydiffractometry.

The results of the X-ray diffraction are indicated at H and I in FIG. 8.

The results of FIG. 8 show that the tetracalcium phosphate obtainedaccording to the present invention can be stably present in an excessivequantity of water.

Example 8

A 20 g quantity of purified water was added to 10 g of powderytetracalcium phosphate. The resulting mixture was subjected to surfacetreatment under the conditions (temperature and time) as shown in Table2 and separated by filtration. The cake was allowed to stand for dryingfor 24 hours, giving powder for setting composition. In Table 2, theFIGS. 1 to 40 designate the sample numbers. Thereafter an aqueoussolution of citric acid at a concentration of 40% was mixed with theabove powder to give setting compositions. The setting time of eachcomposition was determined. The powder was mixed with the aqueoussolution in a powder to liquid ratio of 2.3 g/ml. Table 3 shows theresults.

                  TABLE 2                                                         ______________________________________                                        Treatment      Treatment temperature                                          Time           23° C.                                                                         37° C.                                                                          50° C.                                                                       95° C.                           ______________________________________                                        1      min     1       11       21    31                                      5      min     2       12       22    32                                      10     min     3       13       23    33                                      30     min     4       14       24    34                                      1      hr      5       15       25    35                                      3      hrs     6       16       26    36                                      6      hrs     7       17       27    37                                      12     hrs     8       18       28    38                                      24     hrs     9       19       29    39                                      72     hrs     10      20       30    40                                      ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Sample No.          Setting time                                              ______________________________________                                         1                  Within 20 sec                                              2                  Within 20 sec                                              3                  Within 20 sec                                              4                  Within 20 sec                                              5                  30 sec                                                     6                  1 min                                                      7                  4 min 30 sec                                               8                  4 min 45 sec                                               9                  6 min 15 sec                                              10                  7 min 50 sec                                              11                  Within 20 sec                                             12                  40 sec                                                    13                  1 min 50 sec                                              14                  3 min 45 sec                                              15                  4 min 30 sec                                              16                  4 min 55 sec                                              17                  5 min 10 sec                                              18                  5 min 30 sec                                              19                  6 min 45 sec                                              20                  7 min 40 sec                                              21                  Within 20 sec                                             22                  30 sec                                                    23                  45 sec                                                    24                  2 min                                                     25                  4 min                                                     26                  4 min 20 sec                                              27                  4 min 30 sec                                              28                  4 min 40 sec                                              29                  6 min                                                     30                  7 min 40 sec                                              31                  1 min 30 sec                                              32                  2 min                                                     33                  4 min 45 sec                                              34                  5 min 30 sec                                              35                  5 min 40 sec                                              36                  5 min 45 sec                                              37                  5 min 50 sec                                              38                  6 min                                                     39                  7 min 45 sec                                              40                  11 min 15 sec                                             ______________________________________                                    

Example 9

A 100 g quantity of powdery tetracalcium phosphate was stirred for 3hours in 200 g of distilled water heated to 95° C. and the resultingmixture was subjected to filtration. The cake was dried at 105° C. for24 hours. The obtained powdery tetracalcium phosphate coated withapatite was mixed with aqueous solutions under the following conditions,giving setting compositions:,

(a) the powder was mixed with. an aqueous solution of 40% citric acid ina ratio of the powder/liquid=2.4 (g/ml);

(b) the powder was mixed with an aqueous solution containing 40% citricacid and 5% polyacrylic acid in a ratio of powder/liquid=2.2 (g/ml);

(c) the powder was mixed with an aqueous solution of 38% citric acid, 1%tartaric acid and 2.5% polyacrylic acid in a ratio of powder/liquid=2.2(g/ml);

(d) the powder was mixed with an aqueous solution of 29% citric acid,10% malonic acid and 2.5% polyacrylic acid in a ratio ofpowder/liquid=2.3 (g/ml); and

(e) the powder was mixed with an aqueous solution of 40% citric acid and20% phosphoric acid in a ratio of powder/liquid=2.0 (g/ml).

The setting compositions thus obtained were tested for (1) setting time,(2) compressive strength after 24 hours (kgf/cm²) and (3) filmthickness, all by the test methods according to JIS T6602.

Table 4 shows the results.

                  TABLE 4                                                         ______________________________________                                        Mixing                                                                        conditions (1)            (2)    (3)                                          ______________________________________                                        (a)        6 min 30 sec    984   24 μm                                     (b)        6 min 30 sec   1239   29 μm                                     (c)        5 min 30 sec   1019   38 μm                                     (d)        5 min 30 sec   1123   25 μm                                     (e)        4 min 45 sec   1472   41 μm                                     ______________________________________                                    

Comparison Example 2

Setting compositions were prepared in the same manner as in Example 9with the exception of using tetracalcium phosphate particles not surfacetreated.

Setting compositions were tested by the same methods as in Example 9with the results shown below in Table 5. In Table 5, the symbols (a) to(e) and (1) to (3) have the same meaning as in Table 4.

                  TABLE 5                                                         ______________________________________                                        Mixing                                                                        conditions                                                                              (1)          (2)       (3)                                          ______________________________________                                        (a)       Within 30 sec                                                                              Impossible                                                                              Impossible                                                          to measure                                                                              to measure                                   (b)       Within 30 sec                                                                              Impossible                                                                              Impossible                                                          to measure                                                                              to measure                                   (c)       Within 30 sec                                                                              Impossible                                                                              Impossible                                                          to measure                                                                              to measure                                   (d)       Within 30 sec                                                                              Impossible                                                                              Impossible                                                          to measure                                                                              to measure                                   (e)       Within 30 sec                                                                              Impossible                                                                              Impossible                                                          to measure                                                                              to measure                                   ______________________________________                                    

As clear from the results shown in Table 5, the compositions preparedunder the same mixing conditions as in Example 9 are set within a veryshort period of time, i.e. are set substantially instantaneously, thusfailing to obtain a soft setting composition which is easy to handle.

Comparison Example 3

Setting compositions were produced under the same mixing conditions asin Example 9 except that tetracalcium phosphate not surface treated wereused and that an increased amount of the acidic aqueous solution wasused to obtain setting compositions having physical properties which canbe measured.

The mixing Conditions (f) to (j) in Table 6 are as follows.

(f) the aqueous solution (a) in Example 9 was mixed in a ratio ofpowder/liquid=1.5 (g/ml)

(g) the aqueous solution (b) in Example 9 was mixed in a ratio ofpowder/liquid=1.5 (g/ml)

(h) the aqueous solution (c) in Example 9 was mixed in a ratio ofpowder/liquid=1.5 (g/ml)

(i) the aqueous solution (d) in Example 9 was mixed in a ratio ofpowder/liquid=1.5 (g/ml)

(j) the aqueous solution (e) in Example 9 was mixed in a ratio ofpowder/liquid=1.5 (g/ml)

Table 6 shows the results.

                  TABLE 6                                                         ______________________________________                                        Mixing                                                                        conditions (1)            (2)    (3)                                          ______________________________________                                        (f)        4 min          593    46 μm                                     (g)        3 min 50 sec   612    52 μm                                     (h)        3 min 05 sec   623    73 μm                                     (i)        2 min 40 sec   671    107 μm                                    (j)        1 min 55 sec   819    113 μm                                    ______________________________________                                    

Example 10

Used as a powder material was a powdery tetracalcium phosphate (having amaximum particle size of 20 μm and an average particle size of 5 μm)having a double structure wherein the surface of particles was coatedwith apatite by subjecting the tetracalcium phosphate to hydrationreaction. Used as a liquid material was an acidic aqueous solutioncontaining citric acid and phosphoric acid. Using these materials, asetting composition sample was obtained by mixing the powder materialand the liquid material in a ratio of powder/liquid=2.4 g/ml.

The concentrations of citric acid and phosphoric acid in the liquidmaterial used for preparing the samples were as follows.

No. 41--citric acid=35%, orthophosphoric acid=7%

No. 42--citric acid=40%, orthophosphoric acid=5%

No. 43--citric acid=45%, orthophosphoric acid=5%

No. 44--citric acid=40%, orthophosphoric acid=10%

No. 45--citric acid=35%, orthophosphorlc acid=15%

No. 46--citric acid=40%, orthophosphorlc acid=15%

No. 47--citric acid=45%, orthophosphoric acid=15%

The setting compositions thus obtained were tested for (1) setting time,(2) compressive resistance (kgf/cm²) after 24 hours and (3) filmthickness, all by the test methods according to JIS T 6602.

Table 7 shows the results.

                  TABLE 7                                                         ______________________________________                                               (1)           (2)    (3)                                               ______________________________________                                        No. 41   6 min 10 sec    1130   20 μm                                      No. 42   5 min 50 sec    1231   21 μm                                      No. 43   4 min 45 sec    1339   27 μm                                      No. 44   5 min 20 sec    1828   22 μm                                      No. 45   5 min 10 sec    1243   30 μm                                      No. 46   4 min 50 sec    1619   24 μm                                      No. 47   4 min 5 sec     1283   23 μm                                      ______________________________________                                    

Example 11

Used as a powder material was a mixture of a 100-part of the sameapatite-coated, double-structured tetracalcium phosphate particles as inExample 10, 25 parts of barium sulfate (X-ray contrast medium) and 2.5parts of calcium fluoride (anti-fungus agent). The powder material wasmixed with an acidic aqueous solution containing citric acid andphosphoric acid as a liquid material, giving a setting compositionsample.

Given below are the concentrations of citric acid and phosphoric acid inthe liquid material, and the ratio of the powdery/liquid employed forpreparation of samples.

No. 48--citric acid=42% orthophosphoric acid=10% ratio ofpowder/liquid=2.5 g/ml

No. 49--citric acid=41% orthophosphoric acid=11% ratio ofpowder/liquid=2.6 g/ml

No. 50--citric acid=38%, orthophosphoric acid=8% ratio ofpowder/liquid=2.7 g/ml

The setting compositions thus obtained were tested for (1) setting time,(2) compressive resistance (kgf/cm²) after 24 hours and (3) filmthickness in the same manner as in Example 10.

Table 10 shows the results.

                  TABLE 8                                                         ______________________________________                                               (1)           (2)    (3)                                               ______________________________________                                        No. 48   4 min 30 sec    1654   30 μm                                      No. 49   4 min 40 sec    1792   29 μm                                      No. 50   4 min 20 sec    1823   30 μm                                      ______________________________________                                    

As clear from the results of Tables 7 and 8, the setting time of thesamples Nos. 41 to 50 is in an ideal range of 4 to 8 minutes and thefilm thickness is about 30 μm, which means that the samples are neithertoo hard nor too soft, hence are easy to handle.

Since the average compressive resistance of natural bones is about 1500kgf/cm², evidently the products of the invention have a sufficientstrength for use as their substitutes.

Comparison Example 4

The same apatite-coated, double-structured powdery tetracalciumphosphate as used in Example 10 as a powder material was mixed with anacidic aqueous solution as a liquid material containing citric acid andphosphoric acid, giving a setting composition sample.

The concentrations of citric acid and phosphoric acid in the liquidmaterial and the ratio of powder material to liquid material forpreparation of samples were as follows.

No. 51--citric acid=51%, phosphoric acid=5% powder/liquid ratio=2.0 g/ml

No. 52--citric acid=46% phosphoric acid=26% powder/liquid ratio=2.0 g/ml

No. 53--citric acid=35% phosphoric acid=30% powder/liquid ratio=2.0 g/ml

No. 54--citric acid=30%, phosphoric acid=25% powder/liquid ratio=2.0g/ml

No. 55--citric acid=24%, phosphoric acid=15% powder/liquid ratio=2.2g/ml

No. 56--citric acid=23% phosphoric acid=7% powder/liquid ratio=2.2 g/ml

No. 57--phosphoric acid=10%

powder/liquid ratio=2.4 g/ml

The setting compositions thus obtained were tested for (1) setting time,(2) compressive resistance after 24 hours (kgf/cm²) and (3) filmthickness in the same manner as in Example 10.

Table 9 shows the results.

                  TABLE 9                                                         ______________________________________                                        (1)               (2)       (3)                                               ______________________________________                                        No. 51  Less than 30  Impossible                                                                              Impossible                                            seconds       to measure                                                                              to measure                                    No. 52  Less than 30  Impossible                                                                              Impossible                                            seconds       to measure                                                                              to measure                                    No. 53  Less than 30  Impossible                                                                              Impossible                                            seconds       to measure                                                                              to measure                                    No. 54  Not set       Impossible                                                                              Impossible                                                          to measure                                                                              to measure                                    No. 55  Not set       Impossible                                                                              Impossible                                                          to measure                                                                              to measure                                    No. 56  Not set       Impossible                                                                              Impossible                                                          to measure                                                                              to measure                                    No. 57  Not set       Impossible                                                                              Impossible                                                          to measure                                                                              to measure                                    ______________________________________                                    

As clear from the results of Table 9, when the ratio of citric acid tophosphoric acid in a liquid material is outside the range specified inthe invention, the obtained samples were set in an exceedingly shortperiod of time, or were not cured, or were apparently set, but thehardened products exhibited a fatal defect of, e.g. having substantiallyno mechanical Strength, hence unsuited for use.

Comparison Examples 5 to 8

The following commercially available or known setting compositions formedical or dental use which consisted of powder material and liquidmaterial were checked for physical properties in the same manner as inExample 10.

[Comparison Example 5]

Apatite-coated commercially available product A:

powder material: α-tricalcium phosphate

liquid material: aqueous solution of organic high-molecular weight acidpowder/liquid ratio=1.3 g/g

[Comparison Example 6]

Product disclosed in Japanese Unexamined Patent Publication No.72363/1987:

powder material: tetracalcium phosphate

liquid material: aqueous solution of citric acid powder/liquid ratio=2.0g/g

[Comparison Example 7]

Product disclosed in Japanese Unexamined Patent Publication No.176252/1989:

powder material: tetracalcium phosphate+dibasic calcium phosphate

liquid material: aqueous solution of phosphoric acid powder/liquidratio=3.8 g/g

[Comparison Example 8]

Product disclosed in Japanese Unexamined Patent Publication No.100049/1989

powder material: α-tricalcium phosphate+tetracalcium phosphate

liquid material: aqueous solution of a mixture of citric acid,saccharose and chitosan

powder/liquid ratio=2.0 g/g

The setting compositions thus obtained were tested for (1) setting time,(2) compressive resistance after 24 hours (kgf/cm²) and (3) filmthickness in the same manner as in Example 10.

                  TABLE 10                                                        ______________________________________                                        Comp. Ex.  (1)            (2)    (3)                                          ______________________________________                                        5          6 min 10 sec   541    20 μm                                     6          2 min 50 sec   910    57 μm                                     7          35 min         342    22 μm                                     8          8 min 50 sec   623    39 μm                                     ______________________________________                                    

As clear from the results of Table 10, none of the obtained products hadall of the following properties, namely an appropriate setting time(preferably about 2 to about 10 minutes), a compressive strengthsufficient for use as substitutes for bones, teeth and the like(preferably kgf/cm² or higher), a softness which facilitates handling(preferably film thickness up to 30 μm) and like properties. In general,when any of the products was outstanding in a specific property, butpoor in other properties.

Reference Example 3

FIG. 9 graphically represents the relationships in quantity betweencitric acid and phosphoric acid in the liquid material for settingcompositions of the invention, more specifically the relationshiptherebetween which results in improvement of properties (the rangeaccording to the invention), the relationship therebetween which resultsin increase of compressive strength (more preferred range according tothe invention), and the relationship therebetween which results inhighest degree of increase of compressive strength (most preferred rangeaccording to the invention).

The area surrounded by the outermost line indicates the ordinary rangeof the invention, the area surrounded by the intermediate line indicatesthe preferred range of the invention and the area surrounded by theinnermost line indicates the most preferred range of the invention.

Example 12

The same procedure as in Example 10 was repeated with the exception ofusing citric acid and phosphoric acids in the following ratios, givingsetting compositions wherein the ratio of powder/liquid was 2.4 g/ml.

No. 58--citric acid=40%, pyrophosphoric acid=10%

No. 59--citric acid=40%, polyphosphoric acid=10%

No. 60--citric acid=40%, metaphosphoric acid=10%

No. 61--citric acid=40%, phosphorous acid=10%

The setting compositions thus obtained were tested for (1) setting time,(2) compressive strength (kgf/cm²) after 24 hours and (3) film thickness(μm), in the same manner as in Example 10.

Table 11 shows the results.

                  TABLE 11                                                        ______________________________________                                                         Compressive                                                  Setting time     strength   Thickness                                         ______________________________________                                        No. 58  5 min 10 sec 1750       25                                            No. 59  5 min 15 sec 1782       27                                            No. 60  5 min 45 sec 1611       28                                            No. 61  6 min 10 sec 1815       21                                            ______________________________________                                    

Example 13

Setting compositions were prepared in the same manner as in Example 10except that citric acid and phosphoric acids were used in the followingratios and that the ratios of powder/liquid were as follows.

No. 62--citric acid=25% orthophosphoric acid=5% powder/liquid=3.0 g/ml

No. 63--citric acid=45% phosphorous acid=25% powder/liquid=1.0 g/ml

No. 64--citric acid=30% phosphorous acid=20% powder/liquid=2.2 g/ml

No. 65--citric acid=48%, orthophosphoric acid=5% powder/liquid=2.0 g/ml

The setting compositions thus obtained were tested for (1) setting time,(2) compressive strength (kgf/cm²) after 24 hours and (3) film thickness(μm), in the same manner as in Example 10.

                  TABLE 12                                                        ______________________________________                                                         Compressive                                                  Setting time     strength   Thickness                                         ______________________________________                                        No. 62  7 min 30 sec 1186       11                                            No. 63  7 min 50 sec 1027       12                                            No. 64  6 min 15 sec 1250       24                                            No. 65  4 min 10 sec 1247       26                                            ______________________________________                                    

Table 12 shows the results.

We claim:
 1. A process for preparing tetracalcium phosphate particles,the process comprising the steps of (1) sintering or fusing a powdermixture at a temperature of not lower than 1,400° C., the mixturecomprising a powder of calcium source and a powder of phosphorus sourcein a Ca/P molar ratio of 2:1, and about 0.005 to about 5 parts of analuminum compound, calculated as Al₂ O₃, per 100 parts of tetracalciumphosphate to be produced in terms of the theoretical amount, and (2)finely dividing the obtained product.
 2. A process according to claim 1wherein the calcium source and the phosphorus source are at least onemember selected from the group consisting of CaHPO₄, CaHPO₄.2H₂ O andCa₃ (PO₄)₂.
 3. A process according to claim 1 wherein the calcium sourceis CaCO₃.
 4. A process according to claim 1 wherein the particles of thecalcium source, the phosphorous source and the aluminum compound have aparticle size of up to 20 μm.
 5. A process according to claim 1 whereinthe particles of the calcium source, the phosphorous source and thealuminum compound have a particle size of about 5 μm on the average. 6.A process according to claim 1 wherein the aluminum compound is at leastone member selected from the group consisting of Al₂ O₃, Al(OH)₃,Al(PO)₃, AlPO₄, Al(H₂ PO₄)₃, AlB₂, AlCl₃, AlF₃, AlI₃, Al₂ (SiO₃)₃, Al₂(SO₄)₃ and Al₂ TiO₅.
 7. A process according to claim 1 wherein theamount of the aluminum compound is about 1 to about 2 parts, calculatedas Al₂ O₃, per 100 parts of tetracalcium phosphate to be produced interms of the theoretical amount.
 8. A process according to claim 1wherein the calcining temperature is about 1,500° to about 1,550° C. 9.A process according to claim 1 wherein the aluminum compound, calculatedas Al₂ O₃, contains up to 60% of at least one member selected from thegroup consisting of BaSO₄, BaCO₃, SrSO₄, SrCO₃, BaSiF₆, SnF₆, CaF₂, NaF,AlF₃ and Na₂ SiF₆.
 10. Tetracalcium phosphate particles prepared by theprocess as defined in claim 1.